TY - JOUR
T1 - Combined analysis of antigen presentation and T-cell recognition reveals restricted immune responses in melanoma
AU - Kalaora, Shelly
AU - Wolf, Yochai
AU - Feferman, Tali
AU - Barnea, Eilon
AU - Greenstein, Erez
AU - Reshef, Dan
AU - Tirosh, Itay
AU - Reuben, Alexandre
AU - Patkar, Sushant
AU - Levy, Ronen
AU - Quinkhardt, Juliane
AU - Omokoko, Tana
AU - Qutob, Nouar
AU - Golani, Ofra
AU - Zhang, Jianhua
AU - Mao, Xizeng
AU - Song, Xingzhi
AU - Bernatchez, Chantale
AU - Haymaker, Cara
AU - Forget, Marie Andrée
AU - Creasy, Caitlin
AU - Greenberg, Polina
AU - Carter, Brett W.
AU - Cooper, Zachary A.
AU - Rosenberg, Steven A.
AU - Lotem, Michal
AU - Sahin, Ugur
AU - Shakhar, Guy
AU - Ruppin, Eytan
AU - Wargo, Jennifer A.
AU - Friedman, Nir
AU - Admon, Arie
AU - Samuels, Yardena
N1 - Publisher Copyright:
©2018 American Association for Cancer Research.
PY - 2018/11
Y1 - 2018/11
N2 - The quest for tumor-associated antigens (TAA) and neoantigens is a major focus of cancer immunotherapy. Here, we combine a neoantigen prediction pipeline and human leukocyte antigen (HLA) peptidomics to identify TAAs and neoantigens in 16 tumors derived from seven patients with melanoma and characterize their interactions with their tumor-infiltrating lymphocytes (TIL). Our investigation of the antigenic and T-cell landscapes encompassing the TAA and neoantigen signatures, their immune reactivity, and their corresponding T-cell identities provides the first comprehensive analysis of cancer cell T-cell cosignatures, allowing us to discover remarkable antigenic and TIL similarities between metastases from the same patient. Furthermore, we reveal that two neoantigen-specific clonotypes killed 90% of autologous melanoma cells, both in vitro and in vivo, showing that a limited set of neoantigen-specific T cells may play a central role in melanoma tumor rejection. Our findings indicate that combining HLA peptidomics with neoantigen predictions allows robust identification of targetable neoantigens, which could successfully guide personalized cancer immunotherapies. SIGNIFICANCE: As neoantigen targeting is becoming more established as a powerful therapeutic approach, investigating these molecules has taken center stage. Here, we show that a limited set of neoantigen-specific T cells mediates tumor rejection, suggesting that identifying just a few antigens and their corresponding T-cell clones could guide personalized immunotherapy.
AB - The quest for tumor-associated antigens (TAA) and neoantigens is a major focus of cancer immunotherapy. Here, we combine a neoantigen prediction pipeline and human leukocyte antigen (HLA) peptidomics to identify TAAs and neoantigens in 16 tumors derived from seven patients with melanoma and characterize their interactions with their tumor-infiltrating lymphocytes (TIL). Our investigation of the antigenic and T-cell landscapes encompassing the TAA and neoantigen signatures, their immune reactivity, and their corresponding T-cell identities provides the first comprehensive analysis of cancer cell T-cell cosignatures, allowing us to discover remarkable antigenic and TIL similarities between metastases from the same patient. Furthermore, we reveal that two neoantigen-specific clonotypes killed 90% of autologous melanoma cells, both in vitro and in vivo, showing that a limited set of neoantigen-specific T cells may play a central role in melanoma tumor rejection. Our findings indicate that combining HLA peptidomics with neoantigen predictions allows robust identification of targetable neoantigens, which could successfully guide personalized cancer immunotherapies. SIGNIFICANCE: As neoantigen targeting is becoming more established as a powerful therapeutic approach, investigating these molecules has taken center stage. Here, we show that a limited set of neoantigen-specific T cells mediates tumor rejection, suggesting that identifying just a few antigens and their corresponding T-cell clones could guide personalized immunotherapy.
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U2 - 10.1158/2159-8290.CD-17-1418
DO - 10.1158/2159-8290.CD-17-1418
M3 - Article
C2 - 30209080
AN - SCOPUS:85055912571
SN - 2159-8274
VL - 8
SP - 1366
EP - 1375
JO - Cancer discovery
JF - Cancer discovery
IS - 11
ER -